The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors have emerged as promising targets for therapeutic products.1 TRAIL is expressed on a limited number of cell types (mainly T cells, NK cells, monocytes, dendritic cells, neutrophils) in healthy people. To date, five TRAIL receptors have been identified: TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcR1), TRAIL-R4 (DcR2) and osteoprotegerin (OPG). Of these, only DR4 and DR5 are functional receptors for TRAIL; the other receptors lack the intracellular functional death domain, and act only as decoy receptors. DR4 and DR5 are expressed in a broad range of solid tumors and hematologic malignancies. Binding of homotrimeric TRAIL to either receptor triggers a cascade of activities that leads to apoptosis.2,3 DR4/DR5 trimerizes upon TRAIL binding,3 and the intracellular death domains of trimerized DR4/DR5 are capable of activating caspase 8. Active caspase 8 further activates caspase 3, which digests polypeptides that maintain structural and biochemical integrity of cells.
The TRAIL-induced extrinsic apoptosis pathway is independent of p53,4 which is a critical component of an intrinsic pathway. Conventional treatment of most tumors eventually select for tumor cells that have inactive p53, resulting in resistance to chemotherapy and radiotherapy.5 In these cells, the intrinsic apoptosis pathway is likely diminished A number of reports have also indicated that TRAIL synergizes with conventional anticancer therapies such as irradiation and chemotherapeutic drugs6,7,8 Importantly, TRAIL has been reported to trigger apoptosis in cancer cells while sparing normal cells.9 The unique function of DR4/DR5 and their expression profile have made them a promising candidate for rationally-designed drugs.
Recombinant TRAIL (rTRAIL), which can induce apoptosis of cells that express DR4 or DR5, has been explored as potential therapeutic.10 While rTRAIL activates both DR4 and DR5, its half life is relatively short (1-2 days or less), although it can be engineered as an Fc fusion protein that has an extended half-life. It also exhibits cytotoxicity in hepatocytes and neuronal cells.11 In combination therapies, rTRAIL has been used to sensitize previously resistant cancer cells, but it also sensitizes normal cells in some cases. Some tumor cells are protected from rTRAIL-induced apoptosis, possibly through the expression of decoy receptors. Repeated TRAIL exposure may also induce resistance to cancer cells to TRAIL therapies.12 
An alternative approach involves targeting DR4 or DR5 with therapeutic human monoclonal antibodies (mAbs), which have a long half-life (20 days for IgG1) and tend to have low immunogenicity potential. It is not yet clear whether rTRAIL or an agonistic antibody will be the more efficacious therapy in humans; preclinical and clinical studies with both types of candidate therapeutics are in progress. Several groups have published proof-of-concept studies using murine anti-DR4/DR5 antibodies in animal models.14,15 Preliminary animal studies have demonstrated tumor killing activities by anti-DR4/DR5 antibodies in multiple types of tumors.13,16 Three human antibodies, anti-DR4 mapatumumab (Human Genome Sciences), anti-DR5 lexatumumab (Human Genome Sciences) and anti-DR5 conatumumab (Amgen), are in Phase 2 clinical studies, as is the humanized anti-DR5 tigatuzumab (CS-1008; Daiichi Sankyo).
Combination therapies that include anti-TRAIL receptor agonistic antibodies with other treatments such as paclitaxel, carboplatin, histone deacetylase inhibitor may provide better responses in clinical studies.17,18 Clinical efficacy of the candidates either as a monotherapy or as part of combination therapy, and possible synergies, are currently being tested in Phase 2 and 3 studies. Additional potent human mAbs that target this pathway will find use. The present invention is based, in part, on the identification and characterization of wholly human mAbs specific for DR4.